Abstract:Sixteen compounds (TR1–TR16) were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B inhibition. Compound TR16 was the most potent inhibitor against MAO-B with an IC50 value of 0.17 μM, followed by TR2 (IC50 = 0.27 μM). TR2 and TR16 selectivity index (SI) values for MAO-B versus MAO-A were 84.96 and higher than 235.29, respectively. Compared to the basic structures, the para-chloro substituent in T… Show more
“…Of note, among the two pyridazinone derivatives, SZV-2043 and SZV-2045, only the former, which releases hydrogen peroxide in hAT, was activatory. The lack of hydrogen peroxide-releasing and of 2-DG uptake activating properties of SZV-2045—being a 2-(3-aminopropyl)-3(2 H )-pyridazinone—was consistent with the fact that various pyridazinone derivatives have been described as inhibitors for human SSAO/VAP-1 [ 56 ], and for MAO-B as well [ 57 ].…”
Benzylamine is a natural molecule present in food and edible plants, capable of activating hexose uptake and inhibiting lipolysis in human fat cells. These effects are dependent on its oxidation by amine oxidases present in adipocytes, and on the subsequent hydrogen peroxide production, known to exhibit insulin-like actions. Virtually, other substrates interacting with such hydrogen peroxide-releasing enzymes potentially can modulate lipid accumulation in adipose tissue. Inhibition of such enzymes has also been reported to influence lipid deposition. We have therefore studied in human adipocytes the lipolytic and lipogenic activities of pharmacological entities designed to interact with amine oxidases highly expressed in this cell type: the semicarbazide-sensitive amine oxidase (SSAO also known as PrAO or VAP-1) and the monoamine oxidases (MAO). The results showed that SZV-2016 and SZV-2017 behaved as better substrates than benzylamine, releasing hydrogen peroxide once oxidized, and reproduced or even exceeded its insulin-like metabolic effects in fat cells. Additionally, several novel SSAO inhibitors, such as SZV-2007 and SZV-1398, have been evidenced and shown to inhibit benzylamine metabolic actions. Taken as a whole, our findings reinforce the list of molecules that influence the regulation of triacylglycerol assembly/breakdown, at least in vitro in human adipocytes. The novel compounds deserve deeper investigation of their mechanisms of interaction with SSAO or MAO, and constitute potential candidates for therapeutic use in obesity and diabetes.
“…Of note, among the two pyridazinone derivatives, SZV-2043 and SZV-2045, only the former, which releases hydrogen peroxide in hAT, was activatory. The lack of hydrogen peroxide-releasing and of 2-DG uptake activating properties of SZV-2045—being a 2-(3-aminopropyl)-3(2 H )-pyridazinone—was consistent with the fact that various pyridazinone derivatives have been described as inhibitors for human SSAO/VAP-1 [ 56 ], and for MAO-B as well [ 57 ].…”
Benzylamine is a natural molecule present in food and edible plants, capable of activating hexose uptake and inhibiting lipolysis in human fat cells. These effects are dependent on its oxidation by amine oxidases present in adipocytes, and on the subsequent hydrogen peroxide production, known to exhibit insulin-like actions. Virtually, other substrates interacting with such hydrogen peroxide-releasing enzymes potentially can modulate lipid accumulation in adipose tissue. Inhibition of such enzymes has also been reported to influence lipid deposition. We have therefore studied in human adipocytes the lipolytic and lipogenic activities of pharmacological entities designed to interact with amine oxidases highly expressed in this cell type: the semicarbazide-sensitive amine oxidase (SSAO also known as PrAO or VAP-1) and the monoamine oxidases (MAO). The results showed that SZV-2016 and SZV-2017 behaved as better substrates than benzylamine, releasing hydrogen peroxide once oxidized, and reproduced or even exceeded its insulin-like metabolic effects in fat cells. Additionally, several novel SSAO inhibitors, such as SZV-2007 and SZV-1398, have been evidenced and shown to inhibit benzylamine metabolic actions. Taken as a whole, our findings reinforce the list of molecules that influence the regulation of triacylglycerol assembly/breakdown, at least in vitro in human adipocytes. The novel compounds deserve deeper investigation of their mechanisms of interaction with SSAO or MAO, and constitute potential candidates for therapeutic use in obesity and diabetes.
“…The docking studies revealed that the reason for the potent inhibitory efficiency of compounds 40 and 41 might be due to interaction with some essential residue i.e., E84 and Y326 in MAO-B. Bioavailability prediction studies showed that compounds 40 and 41 have drug-like properties, so they can be considered a candidate for developing MAO-B inhibitors [ 106 ]. Fig.…”
Parkinson’s disease is a neurodegenerative disorder characterized by slow movement, tremors, and stiffness caused due to loss of dopaminergic neurons caused in the brain’s substantia nigra. The concentration of dopamine is decreased in the brain. Parkinson’s disease may be happened because of various genetic and environmental factors. Parkinson’s disease is related to the irregular expression of the monoamine oxidase (MAO) enzyme, precisely type B, which causes the oxidative deamination of biogenic amines such as dopamine. MAO-B inhibitors, available currently in the market, carry various adverse effects such as dizziness, nausea, vomiting, lightheadedness, fainting, etc. So, there is an urgent need to develop new MAO-B inhibitors with minimum side effects. In this review, we have included recently studied compounds (2018 onwards). Agrawal et al
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reported MAO-B inhibitors with IC
50
0.0051 µM and showed good binding affinity. Enriquez et al
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reported a compound with IC
50
144 nM and bind with some critical amino acid residue Tyr60, Ile198, and Ile199. This article also describes the structure–activity relationship of the compounds and clinical trial studies of related derivatives. These compounds may be used as lead compounds to develop potent compounds as MAO-B inhibitors.
Graphic Abstract
“…After demonstrating the validity of the docking protocol, the three most selective MAO-B inhibitors, 6, 2, and 13, and three non-selective MAO-B inhibitors 92, 99, and 111 were docked into the MAO-B active site. For each inhibitor, binding capabilities inside the MAO-B binding site were assessed by: (i) selection of the best pose after performing detailed visual analysis of all five poses generated per ligand in comparison with the native ligand C18, and (ii) essential interactions with critical binding site residues PRO:102, LEU:171, CYS:172, ILE:199, GLN:206, ILE:316, TYR:326, TYR:398, TYR:435 [45][46][47].…”
To facilitate the identification of novel MAO-B inhibitors, we elaborated a consolidated computational approach, including a pharmacophoric atom-based 3D quantitative structure–activity relationship (QSAR) model, activity cliffs, fingerprint, and molecular docking analysis on a dataset of 126 molecules. An AAHR.2 hypothesis with two hydrogen bond acceptors (A), one hydrophobic (H), and one aromatic ring (R) supplied a statistically significant 3D QSAR model reflected by the parameters: R2 = 0.900 (training set); Q2 = 0.774 and Pearson’s R = 0.884 (test set), stability s = 0.736. Hydrophobic and electron-withdrawing fields portrayed the relationships between structural characteristics and inhibitory activity. The quinolin-2-one scaffold has a key role in selectivity towards MAO-B with an AUC of 0.962, as retrieved by ECFP4 analysis. Two activity cliffs showing meaningful potency variation in the MAO-B chemical space were observed. The docking study revealed interactions with crucial residues TYR:435, TYR:326, CYS:172, and GLN:206 responsible for MAO-B activity. Molecular docking is in consensus with and complementary to pharmacophoric 3D QSAR, ECFP4, and MM-GBSA analysis. The computational scenario provided here will assist chemists in quickly designing and predicting new potent and selective candidates as MAO-B inhibitors for MAO-B-driven diseases. This approach can also be used to identify MAO-B inhibitors from other libraries or screen top molecules for other targets involved in suitable diseases.
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